Orofacial clefting is one of the most common birth defects in humans, affecting approximately 1 in 700 live births. This frequency likely stems from the complexity of craniofacial morphogenesis, which requires precise regulation of gene expression changes, alterations in cell physiology and morphogenic movements. Although an increasing number of genes have been linked to cleft lip and cleft palate, the mechanisms governing orofacial malformations remain unclear. The overall objective of this project is to expand our understanding of the genetic basis of orofacial clefting through the use of a novel mouse model of cleft palate. The ENU-induced clfp4 mouse harbors a recessive mutation causing cleft secondary palate, omphalocele and skeletal malformations with high penetrance. While simultaneous presentation of orofacial clefting and body wall defects is observed in human syndromes, there are few mouse models that recapitulate these phenotypes. Preliminary mapping data places the mutation at the distal end of Chromosome 10, a region where this combination of phenotypes has not been reported. Thus, clfp4 likely represents a new model of craniofacial/body wall birth defects. Although preliminary phenotypic analysis has revealed that cleft palate in this mutant results from a failure of palate shelf elevation, efficient design and interpretation of more detailed experiments, such as marker analysis, would be greatly facilitated by identification of the clfp4 causative gene. To develop this unique model of cleft palate and to elucidate the mechanism underlying the phenotype, we propose to identify the gene that underlies the cflp4 mutation through high-resolution genetic mapping and targeted re-sequencing, and perform basic phenotypic analysis to begin to understand the mechanistic basis of the defect. This work will improve our understanding of the molecular networks that regulate palatogenesis, providing a foundation for the development of new methods for the diagnosis, prevention and treatment of cleft palate and other craniofacial disorders. PUBLIC HEALTH RELEVANCE: Orofacial clefting is one of the most common birth defects in humans, affecting 1 in 700 live births. The total health care costs for surgical repair and post-operative therapies is staggering, and the disfigurement of such disorders often have devastating social and psychological consequences for the affected individual. This proposal will expand our understanding of the etiology of orofacial clefting using a novel mouse model of cleft palate and craniofacial malformations, providing a foundation for the development of new methods for the diagnosis, prevention and treatment of cleft palate and other craniofacial disorders.